Thalidomide (N- phthalidoglutarimide) was first synthesized in 1953 by researchers at Chemie Grunenthal in Germany. It was marketed in Europe in 1956 as a sedative/hypnotic drug. Thalidomide is orally administered. It is poorly absorbed in humans. When 100 to 200 milligrams (mg) of thalidomide is ingested by humans, a maximal blood concentration of 0.9 to 1.5 mg/liter is attained 4 to 6 hours later. Thalidomide is extensively distributed throughout the body but does not selectively localize in any tissue. Thalidomide breaks down by spontaneous hydrolysis; however, the hydrolyric cleavage in serum is much slower than in vitro at pH 7.4. This may be due to thalidomide being highly bound to plasma proteins. Thalidomide metabolites are renally excreted. In a series of animal studies, racemic thalidomide has not been toxic. However, side effects in humans have included somnolence, teratogenicity and, upon extended administration, peripheral neuropathy. The teratogenic potential of thalidomide resulted in a variety of malformations of fetuses (phocomelia) and the subsequent removal of thalidomide from the market. The mechanism of the teratogenic effect is not known; however, it will occur when thalidomide is taken between the 35th and 50th day of the menstrual age of the embryo.
In addition to the sedative effect, thalidomide has exhibited an immunomodulatory effect which has resulted in its therapeutic use in the following conditions: rheumatoid arthritis, acute and chronic graft versus host disease, aphthosis, cold hemagglutinin disease, colitis, cutaneous lupus erythematosus, erythema nodosum leprosum, erythema multiform, histiocytosis, immune complex vasculitis, Jessner-Kanof's disease, lichen planus, pemphigoid disorders, photodermatoses, prurigo nodularis, pyoderma gangrenosum, sarcoidosis and Weber Christian's disease. The exact immunomodulatory effect of thalidomide on a molecular level has not been determined; however, a number of observations in this regard have been made. Coulsen et al. (Clin. Exp. Immunol., 7:241, 1970) showed thalidomide derivatives could inhibit production of transformed cells in mixed lymphocyte culture, whereas the lymphocyte response to phytohemagglutinin was not inhibited. In another study by Moncada et al., (Int. J. Leprosy,:53:209,1985) thalidomide was associated with increases in previously suppressed CD4 lymphocyte counts in erythema nodosum leprosum. Thalidomide has also been observed by Sampaio et al. (J. Exp. Med., 173:699, 1991) to inhibit tumor necrosis factor alpha production by stimulated monocytes. Elevated levels of tumor necrosis factor alpha in erythema nodosum leprosumwere reduced by treatment with thalidomide (Sampaio et al., J. Exp. Med., 175:1729, 1992). Tumor necrosis factor alpha has been demonstrated to induce expression of HIV from cell lines (Poli et al., Proc. Nat. Acad. Sci., USA, 87:782, 1990). Blood tumor necrosis factor levels are high in HIV-infected individuals (Lahdevirta et al., Am. J. Med., 85:289, 1988). Thalidomide has been shown to reduce HIV production in peripheral blood mononuclear cells of HIV-infected patients. Thalidomide also inhibited HIV expression from infected cells lines induced with tumor necrosis factor alpha (Schauf et al., Intl. Sci. Conference on Antimicrobial Agents and Chemotherapy, Anaheim, Calif., 1992).
Two million Americans have senile dementia of the Alzheimer's type. It accounts for greater than 50% per cent of dementias in the elderly. About 60% of this population are in long- term care facilities. Alzheimer's disease is the fourth leading cause of death in Americans over the age of 65. The etiology of Alzheimer's disease may be familial in 50% of cases and sporadic in the other 50%. Alzheimer's disease is divided into three clinical stages. Stage one is characterized by a memory loss and emotional instability. The frequency of misdiagnosis at this stage is high. In the second stage, patient confusion increases and although patients are ambulatory, they are at significant risk for falls and accidents. In the last stage of the disease , patients begin to lose control over bodily functions. They become completely dependent on caregivers and are at high risk for development of pneumonia, malnutrition and pressure necrosis of the skin. The patient ultimately goes into a coma and dies. Senile dementia of the Alzheimer's type is characterized by a degenerative process in which there is a loss of cells from the cerebral cortex, hippocampus and subcortical structures. There is the presence of neuritic or senile plaques which are areas of degenerating nerve terminals surrounding cores of aggregated and insoluble protein. This protein, termed .beta.eta-amyloid peptide, is a 40 to 42 amino acid peptide derived from a larger amyloid precursor protein. Many researchers believe that excessive deposition of this toxic protein in the brain results in tissue damage and the development of Alzheimer's disease. However evidence has been recently put forward that Alzheimer's disease may be a chronic inflammatory disorder similar to arthritis. .beta.eta-amyloid deposits in the brain may trigger an inflammatory response resulting in the destruction of both damaged and healthy nerve tissue (Schnabel, Science, 260:1719, 1993).
A number of investigators have observed that the brains of patients with Alzheimer's disease exhibit many of the classical markers of immune-mediated damage. These have included increased numbers of microglia (cells believed to be the functional equivalent to macrophages in the central nervous system) (Stryren et al., Exp. Neurel., 110:93, 1990) and astrocytes expressing inflammatory reactants interleukin 1 and alpha 1 antichymotrypsin (Abraham et al., Cell, 52:487, (1988). Complement proteins of the classical pathway have been immunohistochemically detected in Alzheimer's brain tissue and are most often associated with the .beta.eta amyloid plaques. Rogers et al., (Proc. Nat. Acad. Sci., USA, 89:10016, 1992) presented evidence that .beta.eta amyloid protein activates the classical complement pathway without mediation of immunoglobulin, thereby contributing to the development of the inflammatory process. In another study by Fillit et al., (Neurosci. Lett., 129:318, 1991) levels of tumor necrosis factor alpha were measured in both patients with Alzheimer's disease and age-matched controls by enzyme-linked immunosorbent assay and cytotoxicity bioassay.
The authors reported elevated levels of tumor necrosis factor in Alzheimer's patients compared to controls and indicated elevated circulating tumor necrosis factor may be derived from the local central nervous system inflammatory reaction found in Alzheimer's patients and may account for some of the systemic manifestations of Alzheimer's disease such as weight loss.
McGeer hypothesized that if this inflammatory reaction was an important part of the pathology of Alzheimer's disease, then patient groups with autoimmune diseases such as rheumatoid arthritis who are on a course of anti-inflammatory drugs for a prolonged period of time should have a reduced incidence of Alzheimer's disease. McGeer et al., (Lancet, 335:1037, 1990) retrospectively reviewed hospital data covering 12,000 patients over the age of 64 to determine the prevalence of Alzheimer's disease in rheumatoid arthritis patients. They found that while the prevalance of Alzheimer's disease in the general population was taken to be 2.7%., only 0.39% of those patients with rheumatoid arthritis also had Alzheimer's disease. These data could be interpreted to indicate that anti-inflammatory therapy in patients with rheumatoid arthritis resulted in an unusually low prevalence of Alzheimer's disease. In another study by McGeer et al., (Dementia, 3:146, 1992) of 4000 leprosy patients there was 2.9% incidence of dementia in those patients taking the leprosy drug Dapsone which has an anti-inflammatory effect versus an incidence of 6.25% in those lepers who had not taken Dapsone for five years. These results indicate the possibility that anti-inflammatory drugs may have an effect on the development of Alzheimer's disease. As previously stated, thalidomide has an inhibitory effect on the synthesis of tumor necrosis factor alpha, a mediator of the inflammatory reaction and which is elevated in the sera of Alzheimer's patients (Fillit, Neurosci. Lett., 129:318, 1991). Corder et al (Sci 261: 921, 1993) have discovered an association between Alzheimer's disease and the apolipoprotein E locus on human chromosome 19. Apolipoprotein E (APOE) is a protein that transports cholesterol through the blood stream. APOE has three alleles, APOE-.epsilon.2, APOE-.epsilon.3 and APOE-.epsilon.4. Risk for late onset Alzheimer's disease, which starts after age 65 and comprises three quarters of all cases, increased from 20% to 90% and the mean age of onset decreased from 84 to 68 years in patients with an increasing number of APOE-.epsilon.4 alleles. The APOE-.epsilon.4 allele may either have an active pathogenic role in Alzheimer's disease development or may only be closely linked on chromosome 19 to a gene that does. However it is unusual in the case of a genetic linkage for the APOE gene dose to be correlated with development of Alzheimer's disease. APOE-4 binds more rapidly and tighter to beta amyloid than other APOE's and it is hypothesized that APOE-4 causes soluble circulating beta-amyloid to become insoluble upon binding to it and thereby facilitating beta-amyloid deposition in brain tissue resulting in plaque formation. Soluble beta-amyloid also binds to another apolipoprotein, APOJ. It has been hypothesized that binding to APOJ protects beta-amyloid's solubility and that the amount of APOE-4 versus APOJ is in a delicate balance in the brain with Alzheimer's disease developing if the APOE gene dose is able to shift the balance in favor of APOE-4. APOE-4 also binds to the neurofibrillary tangles found in the brain tissue of patients with Alzheimer's disease. The significance of this is not clear at this time. Progress of Alzheimer's disease is believed to be attributed to degeneration of certain nerve tracts in the central nervous system, resulting in the loss of associated functions. Pathological studies indicate that brains of Alzheimer's patients have loss of several neurotransmitter systems, related to different functions, but the system which is implicated the most is the cholinergic system. Studies show that several important cholinergic tracts innervating the cortical and hippocampal regions degenerate. Although this particular degeneration may not account for all the symptoms of Alzheimer's, it may account for the cognitive and memory deficits, which are some of the most difficult symptoms for patients and their families to deal with. The prior art is silent regarding the treatment of cognitive disorders with thalidomide.